Pre-exposure prophylaxis (PrEP) is a highly efficacious HIV prevention tool for men who have sex with men (MSM). Although research has identified MSM most likely to benefit from PrEP, the intervention's impact on population HIV incidence during real-world implementation is unknown. Identifying novel strategies to evaluate PrEP implementation and maximize the intervention's influence on community HIV transmission rates is critical to improve the cost-effectiveness of this expensive HIV prevention strategy. To address these needs, we will develop a method to evaluate PrEP implementation and identify optimal PrEP prioritization strategies that: (1) maximize clinical benefit to most-at-risk MSM, (2) are highly cost-effective, and (3) bring community HIV transmission to low levels. An innovative aspect of the proposed work is the use of a novel microsimulation technique known as agent-based modeling to evaluate a real-world, statewide PrEP implementation program. Our primary aim is to determine the demographic and behavioral characteristics of MSM who, if prescribed PrEP, would produce the largest decreases in community HIV incidence. Our primary hypothesis is that PrEP strategies prioritizing potential core transmitters (individuals who bridge infectious persons with lower-risk MSM populations) will be more effective at reducing HIV incidence and achieve greater cost-effectiveness than allocation strategies informed by current CDC guidelines. Second, we aim to increase the impact of Rhode Island's (RIs) first and only PrEP implementation program on community HIV transmission. Using the population-based microsimulation, we will evaluate the extent to which adherence, retention in care, and risk compensation (increased risk behavior) influence the program's projected impact on HIV incidence. Finally, we will compare the cost-effectiveness of current versus optimal PrEP implementation strategies. Our multidisciplinary team (with expertise in infectious disease medicine, epidemiology, and mathematical modeling) will leverage unprecedented access to population-based data sources from the state health department, an HIV care provider serving over 80% of the HIV-infected population in RI, the state's publicly-funded sexually transmitted diseases clinic, and the statewide PrEP program to parameterize high resolution, individual-based models. Our results will improve public health decision-making and clinical risk stratification schemes for predicting which MSM should be prioritized for PrEP. Finally, this exploratory R21 project will lay the groundwork for a statewide intervention to identify, engage, and retain potential core transmitters (and other high- risk MSM) in a PrEP program.